Functional and Metabolomic Consequences of K ATP Channel Inactivation in Human Islets

Diabetes. 2017 Jul;66(7):1901-1913. doi: 10.2337/db17-0029. Epub 2017 Apr 25.

Abstract

Loss-of-function mutations of β-cell KATP channels cause the most severe form of congenital hyperinsulinism (KATPHI). KATPHI is characterized by fasting and protein-induced hypoglycemia that is unresponsive to medical therapy. For a better understanding of the pathophysiology of KATPHI, we examined cytosolic calcium ([Ca2+] i ), insulin secretion, oxygen consumption, and [U-13C]glucose metabolism in islets isolated from the pancreases of children with KATPHI who required pancreatectomy. Basal [Ca2+] i and insulin secretion were higher in KATPHI islets compared with controls. Unlike controls, insulin secretion in KATPHI islets increased in response to amino acids but not to glucose. KATPHI islets have an increased basal rate of oxygen consumption and mitochondrial mass. [U-13C]glucose metabolism showed a twofold increase in alanine levels and sixfold increase in 13C enrichment of alanine in KATPHI islets, suggesting increased rates of glycolysis. KATPHI islets also exhibited increased serine/glycine and glutamine biosynthesis. In contrast, KATPHI islets had low γ-aminobutyric acid (GABA) levels and lacked 13C incorporation into GABA in response to glucose stimulation. The expression of key genes involved in these metabolic pathways was significantly different in KATPHI β-cells compared with control, providing a mechanism for the observed changes. These findings demonstrate that the pathophysiology of KATPHI is complex, and they provide a framework for the identification of new potential therapeutic targets for this devastating condition.

MeSH terms

  • Alanine / metabolism
  • Calcium / metabolism*
  • Carbon Isotopes
  • Case-Control Studies
  • Congenital Hyperinsulinism / genetics
  • Congenital Hyperinsulinism / metabolism*
  • Congenital Hyperinsulinism / surgery
  • Female
  • Flow Cytometry
  • Gene Expression
  • Glucose / metabolism*
  • Glutamine / biosynthesis
  • Glycine / biosynthesis
  • Glycolysis / genetics
  • Humans
  • Immunohistochemistry
  • Infant
  • Infant, Newborn
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / ultrastructure
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / ultrastructure
  • KATP Channels / genetics
  • KATP Channels / metabolism
  • Male
  • Metabolomics
  • Microscopy, Electron, Transmission
  • Mutation
  • Oxygen Consumption*
  • Pancreatectomy
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • RNA, Messenger / metabolism
  • Sequence Analysis, RNA
  • Serine / biosynthesis
  • Sulfonylurea Receptors / genetics
  • Sulfonylurea Receptors / metabolism*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • ABCC8 protein, human
  • Carbon Isotopes
  • Insulin
  • KATP Channels
  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying
  • RNA, Messenger
  • Sulfonylurea Receptors
  • Glutamine
  • Serine
  • gamma-Aminobutyric Acid
  • Glucose
  • Alanine
  • Calcium
  • Glycine